This application claims the priority of U.S. Application No. 60/294,438, filed May 30, 2001.
The present invention relates to methods for treating certain fibrotic diseases or other indications.
Glucose and other sugars react with proteins by a non-enzymatic, post-translational modification process called non-enzymatic glycosylation. At least a portion of the resulting sugar-derived adducts, called advanced glycosylation end products (AGEs), mature to a molecular species that is very reactive, and can readily bind to amino groups on adjacent proteins, resulting in the formation of AGE cross-links between proteins. Recently a number of classes of compounds have been identified whose members inhibit the formation of the cross-links, or in some cases break the cross-links. These compounds include, for example, the thiazolium compounds described in U.S. Pat. No. 5,853,703. As AGEs, and particularly the resulting cross-links, are linked to several degradations in body function linked with diabetes or age, these compounds have been used, with success, in animal models for such indications. These indications include loss of elasticity in blood vasculature, loss of kidney function and retinopathy.
Now, as part of studies on these compounds, it has been identified that these compounds inhibit the formation of bioactive agents, such as growth factors and inflammatory mediators, that are associated with a number of indications. These agents include vascular endothelial growth factor (VEGF) and TGF[beta]. As a result, a number of new indications have been identified for treatment with agents that inhibit the formation of, or more preferably break, AGE-mediated cross-links. It is not unreasonable to infer that the effects seen are due to the removal of AGE-related molecules that provide a stimulus for the production or release of these growth factors. Removal of such molecules is believed to proceed in part due to the elimination of AGE-related cross-links that lock the AGE-modified proteins in place. Moreover, such compounds also reduce the expression of collagen in conditions associated with excess collagen production. Regardless of the mechanism, now provided are new methods of treating a number of indications.
In one embodiment, the invention relates to a method of treating or ameliorating or preventing an indication of the invention in an animal, including a human, comprising administering an effective amount of a compound of the formula I: 
wherein: W and Y are independently N or, respectively, CRW or CRY. Z is O, S or NRZ. Q is xe2x80x94CH2xe2x80x94 or xe2x80x94(CO)xe2x80x94CH2xe2x80x94, where the methylene is bonded to a ring nitrogen. RW and RY are independently hydrogen, alkyl, xe2x80x94Cxe2x89xa1CRE, xe2x80x94CH2xe2x80x94Cxe2x89xa1CRP, alkenyl, aryl, arylalkyl, aryloxy, arylthio, amino, alkylamino, arylamino, dialkylamino, diarylamino, CH3C(O)NHxe2x80x94, fluoroalkyl, perfluoroaryl, hydroxyalkyl, C(O)NH2, and S(O)2NH2 or, together with their ring carbon atoms form a fused 6-membered aromatic or heteroaromatic ring, wherein RE or RP is alkyl, hydrogen, hydroxyalkyl or aryl. RZ is alkyl, xe2x80x94CH2xe2x80x94Cxe2x89xa1CRP, aryl, arylalkyl, or aroylalkyl. R1 and R2 are independently hydrogen, alkyl or hydroxymethyl. R3 is hydrogen or methyl. R4 is acetamido, hydrogen, methyl, amino, xe2x80x94Cxe2x89xa1CRE, xe2x80x94CH2xe2x80x94Cxe2x89xa1xe2x80x94CRP alkylthio, fluoromethyl, difluoromethyl, trifluoromethyl, cyanomethyl, hydroxyalkyl, alkoxycarbonyl-methyl, 1-(alkoxycarbonyl)-1-hydroxyalkyl or aminocarbonylmethyl. (The xe2x80x9c1xe2x80x9d notations of xe2x80x9c1-(alkoxycarbonyl)-1-hydroxyalkylxe2x80x9d indicates that a terminal methyl [but for the recited substitutions] of xe2x80x9calkylxe2x80x9d is substituted with the hydroxyl and esterified carbonyl.)